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@ARTICLE{Shirahata:136811,
      author       = {M. Shirahata and T. Ono and D. Stichel$^*$ and D.
                      Schrimpf$^*$ and D. E. Reuss$^*$ and F. Sahm$^*$ and C.
                      Koelsche$^*$ and A. Wefers$^*$ and A. Reinhardt$^*$ and K.
                      Huang$^*$ and P. Sievers$^*$ and H. Shimizu and H. Nanjo and
                      Y. Kobayashi and Y. Miyake and T. Suzuki and J.-I. Adachi
                      and K. Mishima and A. Sasaki and R. Nishikawa and M.
                      Bewerunge-Hudler$^*$ and M. Ryzhova and O. Absalyamova and
                      A. Golanov and P. Sinn and M. Platten and C. Jungk and F.
                      Winkler$^*$ and A. Wick$^*$ and D. Hänggi and A. Unterberg
                      and S. Pfister$^*$ and D. Jones$^*$ and M. van den Bent and
                      M. Hegi and P. French and B. G. Baumert and R. Stupp and T.
                      Gorlia and M. Weller and D. Capper$^*$ and A. Korshunov$^*$
                      and C. Herold-Mende and W. Wick$^*$ and D. N. Louis and A.
                      von Deimling$^*$},
      title        = {{N}ovel, improved grading system(s) for {IDH}-mutant
                      astrocytic gliomas.},
      journal      = {Acta neuropathologica},
      volume       = {136},
      number       = {1},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2018-01249},
      pages        = {153 - 166},
      year         = {2018},
      abstract     = {According to the 2016 World Health Organization
                      Classification of Tumors of the Central Nervous System (2016
                      CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade
                      II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade
                      III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and
                      WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably,
                      IDH gene status has been made the major criterion for
                      classification while the manner of grading has remained
                      unchanged: it is based on histological criteria that arose
                      from studies which antedated knowledge of the importance of
                      IDH status in diffuse astrocytic tumor prognostic
                      assessment. Several studies have now demonstrated that the
                      anticipated differences in survival between the newly
                      defined AIIIDHmut and AAIIIIDHmut have lost their
                      significance. In contrast, GBMIDHmut still exhibits a
                      significantly worse outcome than its lower grade IDH-mutant
                      counterparts. To address the problem of establishing
                      prognostically significant grading for IDH-mutant astrocytic
                      gliomas in the IDH era, we undertook a comprehensive study
                      that included assessment of histological and genetic
                      approaches to prognosis in these tumors. A discovery cohort
                      of 211 IDH-mutant astrocytic gliomas with an extended
                      observation was subjected to histological review, image
                      analysis, and DNA methylation studies. Tumor group-specific
                      methylation profiles and copy number variation (CNV)
                      profiles were established for all gliomas. Algorithms for
                      automated CNV analysis were developed. All tumors exhibiting
                      1p/19q codeletion were excluded from the series. We
                      developed algorithms for grading, based on molecular,
                      morphological and clinical data. Performance of these
                      algorithms was compared with that of WHO grading. Three
                      independent cohorts of 108, 154 and 224 IDH-mutant
                      astrocytic gliomas were used to validate this approach. In
                      the discovery cohort several molecular and clinical
                      parameters were of prognostic relevance. Most relevant for
                      overall survival (OS) was CDKN2A/B homozygous deletion.
                      Other parameters with major influence were necrosis and the
                      total number of CNV. Proliferation as assessed by mitotic
                      count, which is a key parameter in 2016 CNS WHO grading, was
                      of only minor influence. Employing the parameters most
                      relevant for OS in our discovery set, we developed two
                      models for grading these tumors. These models performed
                      significantly better than WHO grading in both the discovery
                      and the validation sets. Our novel algorithms for grading
                      IDH-mutant astrocytic gliomas overcome the challenges caused
                      by introduction of IDH status into the WHO classification of
                      diffuse astrocytic tumors. We propose that these revised
                      approaches be used for grading of these tumors and
                      incorporated into future WHO criteria.},
      cin          = {G380 / L101 / W110 / G370 / B062 / L201},
      ddc          = {610},
      cid          = {I:(DE-He78)G380-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)W110-20160331 / I:(DE-He78)G370-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)L201-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29687258},
      doi          = {10.1007/s00401-018-1849-4},
      url          = {https://inrepo02.dkfz.de/record/136811},
}